Post on 21-Aug-2020
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Web Appendix 8
Review of iron supplementation in pregnancy and childhood
H.P.S. Sachdev and Siddhartha Gogia
Division of Pediatrics and Clinical Epidemiology, Sitaram Bhartia Institute of Science and Research, B-16 Qutab Institutional Area, New Delhi 110 016, India.
From a public health perspective, iron deficiency is believed to be the most important
causal factor for anemia. Consequently, in public health terminology, the terms ‘anemia’,
‘iron deficiency anemia’, and ‘iron deficiency’ are often used interchangeably. With this
background, iron deficiency is believed to be the most common nutritional disorder
globally. Over 30% of the world’s population (~2 billion) is anemic, mainly due to iron
deficiency [1-3]. In developing countries about 50% pregnant women and about 40% of
preschool children are estimated to be anemic [1-3]. On the basis of animal data, and
cross-sectional and longitudinal observational studies in infants, children, adolescents,
and adults several biological consequences have been attributed to iron deficiency. These
include poor pregnancy outcome, impaired physical and cognitive development, and
increased risk of morbidity in children and reduced work productivity in adults. However,
evidence from iron intervention trials has not consistently supported all these inferences.
The primary objective of this review is to update comprehension about the specific role
of iron supplementation in improving maternal and child health, especially in the context
of less developed countries. The ensuing discussion therefore primarily focuses on
evidence obtained from iron intervention trials in relation to biological advantages or
adverse consequences.
Methodology
Literature search was conducted using the search words “iron” and limited to “clinical
trial”, “review”, “meta-analysis”, “systematic review”, “randomized controlled trial” and
“humans”. This search was conducted on several databases including PubMed, Extended
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Medline, Cochrane Controlled Trial Register, OVID, DARE, CINAHL, HEALTHSTAR
and EMBASE. The references mentioned in the above studies and reviews were also
searched for identifying relevant trials and reviews. An effort was also made to obtain
unpublished studies pertaining to the topic by searching relevant databases and contacting
researchers working in the field, and donor and funding agencies. Using the above-
mentioned strategy, approximately 3000 studies were identified and their abstracts
obtained. These abstracts were studied to scrutinize the relevant trials. Wherever
necessary, the full text of the trial was obtained to clarify whether the study could be
included in the final analysis or not. The full text of the trials hence identified was
obtained and all randomized placebo-controlled trials or trials with a factorial design
where the only difference between the experimental group and the control group was iron
were included. The trials were grouped according to the outcome variables, namely,
anemia, infection, physical growth, motor and mental development, physical
performance, morbidity and mortality. In addition, trials comparing daily and intermittent
iron supplementation were also evaluated. The data from the relevant trials was collected
using a pre-tested data abstraction form. If there were no randomized controlled trials
available for certain outcomes, weaker quality of evidence was reported.
Recent high-quality systematic reviews, several of them conducted by our group, were
available for most of the outcome measures. We therefore are presenting our results as an
overview of this evidence, which has been supplemented with other relevant trials that
may have become available after these systematic reviews
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Efficient Indicators of Population Response to Iron Interventions
Governments and donor agencies have implemented pilot and large-scale iron
supplementation and fortification programs globally. However, there has been no
consensus on the best choice of indicators to monitor population response to these
interventions. A pooled analysis [4] was conducted on data from nine randomized iron
intervention trials in seven countries (sample sizes: controls – 909 and intervention –
991) to determine which of the following indicator(s) of iron status showed the largest
response in a population: hemoglobin (Hb), ferritin, transferrin receptor (TfR), zinc
protoporphyrin (ZPP), mean cell volume (MCV), transferrin saturation (TS), and total
body-iron store. Three of the studies were conducted among non-pregnant women, 2
among pregnant women, 2 among preschool-aged children, and 2 among school-aged
children. The interventions lasted between 4 and 18 months, and the intensity of
interventions ranged between low-level fortifications doses to high-level therapeutic
doses. For the purpose of measuring the population response to an iron intervention, the
best indicator of iron deficiency was considered to be one that showed the largest and
most consistent change in response to an increase in bio-available iron intake. For
comparability within the studies and the various indicators, the authors expressed the
change in each indicator in response to the iron intervention in SD units (SDU). Ferritin
increased by > 0.2 SDU in all trials and was significant in 7. Hb changed by > 0.2 SDU
in 6 and was significant in 5. TfR increased by > 0.2 SDU in 5 of 8 interventions in
which it was measured and was significant in 4. ZPP increased by > 0.2 SDU and was
significant in 3 of 6 interventions. Excluding Hb, the indicator with the largest change in
SDU was ferritin in 4 trials, TS in 2 trials, body-iron store in 2 trials, and TfR in 1. In the
2 cases in which body-iron stores showed the largest change, the change in ferritin was
nearly as large. Thus ferritin showed larger and more consistent response to iron
interventions than ZPP or TfR, and a confident inference could not be made about MCV
or TS, which were included in only 4 and 2 trials, respectively. In no case would a
significant change in iron status due to the intervention have gone undetected if Hb and
ferritin had been the only two indicators measured. It is possible that the optimal
indicator(s) may have varied with age, sex, and pregnancy. However, there were too few
trials in each age and sex group to explore this possibility. Thus, hemoglobin and ferritin
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are currently the most efficient combination of indicators for monitoring population
response to iron interventions, and these may have economic and logistic benefits in less
developed countries.
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Biological Consequences of Iron Deficiency in Infants, Children and Adolescents Assessed by Iron Interventions
Hemoglobin and Anemia
A recent systematic review [5] evaluated change in hemoglobin levels with randomized
controlled trials that included oral or parenteral iron supplementation, or iron fortified
formula milk or cereals. Fifty-five trials (56 cohorts) had relevant information; pooled
data was available on 12179 children, 6579 of whom received iron while 5600
constituted the placebo group. Publication bias was evident (p<0.001). The pooled
estimate (random effects model) for change in hemoglobin with iron supplementation
(weighted mean difference) was 0.74 g/dL (95% confidence interval 0.61–0.87, p<0.001;
p<0.001 for heterogeneity). Lower baseline hemoglobin level, oral medicinal iron
supplementation, and malarial non-hyperendemic region were significant predictors of
greater hemoglobin response, and heterogeneity. Projections suggested that on average
between 38% and 62% of baseline anemia (hemoglobin < 11g/dL) is responsive to iron
supplementation among children under six years old; the corresponding range for
malarial hyperendemic regions is 6% – 32%. Thus, iron supplementation increases
hemoglobin levels in children significantly, but modestly. The rise is greater with
baseline anemia, and lower in malarial hyperendemic areas and in those consuming iron
fortified food. The projected reductions in prevalence of anemia with iron
supplementation alone (38% to 62% in non-malarial regions, and 6% to 32% in malarial
hyper-endemic areas) highlight the need for additional area-specific interventions,
particularly in malarial regions.
Mental and Motor Development
A systematic review determined the effects of iron therapy on psychomotor development
and cognitive function in iron deficient children less than 3 years of age [6]. Studies were
included if children less than 3 years of age with evidence of iron deficiency anemia were
randomly allocated to iron or iron and vitamin C versus a placebo or vitamin C alone and
assessment of developmental status or cognitive function was carried out using
standardized tests by observers blind to treatment allocation. Five trials, including 180
children with iron deficiency anemia, examined the effects of iron therapy on measures of
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psychomotor development between 5 and 11 days of commencement of therapy. Data
from four trials could be pooled. The pooled difference in pre to post treatment change in
Bayley Scale psychomotor development index between iron treated and placebo groups
was -3.2 (95% CI -7.24, 0.85) and in Bayley Scale mental development index, 0.55 (95%
CI -2.84, 1.75). Two studies, including 160 randomized children with iron deficiency
anemia, examined the effects of iron therapy on measures of psychomotor development
more than 30 days after commencement of therapy. One trial reported the mean number
of skills gained after two months of iron therapy, using the Denver test. The intervention
group gained 0.8 (95% CI -0.18, 1.78) more skills on average than the control group.
Another study showed that the difference in pre to post treatment change in Bayley Scale
psychomotor development index between iron treated and placebo groups after 4 months
was 18.40 (95%CI 10.16, 26.64) and in Bayley Scale mental development index, 18.80
(95% CI 10.19, 27.41).
Another systematic review evaluated the effect of iron supplementation on mental and
motor development in children through randomized controlled trials employing
interventions that included oral or parenteral iron supplementation, fortified formula
milk, or cereals [7]. The outcomes studied were mental and motor development scores,
and various individual development tests employed, including Bayley mental and
psychomotor development indices, and intelligence quotient. A comprehensive mental
development score was created, which refers to a logical combination of different tests
that assess the same aspect of mental development, namely, Bayley Mental Development
Index (MDI), Stanford Binet Test, Peabody Picture Vocabulary Tests, intelligence
quotient, and cognition scores. Fifteen studies conducted on 2827 children, 1412 of
which received iron and 1415 placebo, were included in this analysis. The pooled
estimate (random effects model) of mental development score standardized mean
difference (SMD) was 0.30 (95% confidence interval 0.15 to 0.46, p<0.001; p<0.001 for
heterogeneity). Initial anemia and iron deficiency anemia were significant explanatory
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variables for heterogeneity. The pooled estimate of Bayley Mental Development Index
(weighted mean difference) in younger children (8 studies on children <27 months old)
was 0.95 (95% CI -0.56 to 2.46, p=0.22; p=0.016 for heterogeneity). For intelligence
quotient scores (4 trials on subjects >8 years age), the pooled SMD was 0.41 (95% CI
0.20 to 0.62, p<0.001; p=0.07 for heterogeneity). Amongst the ten trials evaluating motor
development, eight used Bayley psychomotor development index, one assessed
psychomotor development through DDST, and one used a physical activity score (data on
1246 children; 630 received iron and 616 placebo). There was no effect of iron
supplementation on motor development score (SMD 0.09, 95% CI -0.08 to 0.26, p=0.28;
p=0.028 for heterogeneity). Thus, iron supplementation improves mental development
score modestly (SMD of 0.3, equivalent to 1.5 to 2 points on a scale of 100). This effect
is particularly apparent for intelligence tests above seven years of age, and in initially
anemic or iron deficient anemic subjects. There is no convincing evidence that iron
treatment has an effect on mental development in children below 27 months of age, or on
motor development. However, (i) confidence intervals suggest that these results could be
compatible with moderate positive or adverse effects of iron therapy, (ii) the possibility
of irreversible structural brain changes, particularly in younger children cannot be
excluded due to paucity of relevant preventive trials, and (iii) the effect of longer term
treatment is unclear.
After publication of the above systematic review [7], other relevant trials have appeared
in the literature. In a longitudinal study [8] designed to evaluate the long lasting effect of
iron deficiency on the functioning of auditory and visual systems, healthy Chilean
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children were compared with peers who had received therapy for iron deficiency anemia.
Absolute latencies for all auditory brainstem response waves and inter-peak latencies
(except I–III interval) were significantly longer in formerly anemic children. Longer
latency was also observed for the P100 wave on visual evoked potential. These findings
suggest that untreated iron deficiency in children may have long lasting consequences.
A pertinent review of the additional relevant randomized controlled trials published after
the systematic review [7], is summarized in Table I [9-14]. A trial from Zanzibar [15]
was excluded, as the intervention comprised both iron and folic acid. Amalgamation of
these findings from the additional trials does not alter the broad conclusions of the earlier
systematic review [7]. However, there is a suggestion of an improvement in subtle
developmental measures like oddity learning test and orientation engagement, which are
not encompassed by the traditional tests.
Physical Growth In meta-analyses of randomized controlled intervention trials conducted to assess the
effects of vitamin A, iron, and multi-micronutrient interventions on the growth of
children <18 years old, 21 iron intervention studies that met the design criteria were
identified [16]. Iron interventions had no significant effect on child growth. Overall effect
sizes were 0.09 (95% CI: -0.07, 0.24) for height and 0.13 (95% CI: -0.05, 0.30) for
weight. The results were similar across categories of age, duration of intervention, mode
and dosage of intervention, and baseline anthropometric status. Iron interventions did
result in a significant increase in hemoglobin (Hb) concentrations with an effect size of
1.49 (95% CI: 0.46, 2.51).
More recently, the effect of iron supplementation on physical growth in children was
evaluated through a systematic review of randomized controlled trials employing
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interventions that included oral or parenteral iron supplementation, fortified formula
milk, or cereals [17]. Twenty-five trials (26 cohorts) had relevant information. There was
no evidence of publication bias. The pooled estimates (random effects model) did not
document a statistically significant (P>0.05) positive effect of iron supplementation on
any anthropometric variable: weight for age (4327 children, 2329 of whom received iron
while 1998 constituted the placebo group; standardized mean difference (SMD) 0.11,
95% CI -0.01, 0.23, p=0.061, p<0.001 for heterogeneity), weight for height (1246
children, 626 of whom received iron while 620 constituted the placebo group; SMD 0.21,
95% CI -0.09, 0.52, p=0.170, p<0.001 for heterogeneity), height for age (3935 children,
2132 of whom received iron while 1803 constituted the placebo group; SMD 0.01, 95%
CI = -0.10, 0.12, p=0.795, p<0.001 for heterogeneity), mid upper arm circumference
(1163 children, 538 of whom received iron while 525 constituted the placebo group;
SMD 0.0, 95% CI -0.20, 0.20, p=0.991), skinfold thickness, and head circumference.
Significant heterogeneity was evident, and it’s predictors included greater weight for age
in supplemented children in malarious regions, greater weight for height for children
above 5 years of age, but a negative effect on linear growth in developed countries and
with supplementation for 6 months or longer. In the minority of studies showing benefit,
this was primarily in the children with iron deficiency at baseline. A study suggested that
iron supplementation in young children without iron deficiency may jeopardize optimal
height and weight gains during this period. Thus, there is no convincing evidence of a
positive effect of iron supplementation on the physical growth of children. The identified
predictors of heterogeneity should be considered as exploratory requiring confirmation
and not conclusive.
Physical Performance
The effect of iron supplementation on physical performance in children was evaluated
through a systematic review of randomized controlled trials employing interventions that
included oral or parenteral iron supplementation, fortified formula milk, or cereals [18].
Only three studies could be included, and in all of them oral medicinal iron was used. In
the three studies, heart rates measured after exercise at three different running speeds
were combined. At 5, 6 and 7 miles per hour running speeds, the pooled weighted mean
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(95% CI) difference (WMD) in the heart rates (per minute) between the iron and the
placebo, following exercise were –7.3 (-19.6, 4.9; P= 0.241), -6.6 (-19.9, 6.6; P=0.327),
and –8.0 (-19.7, 3.7; P=0.182). After excluding the study with non-anemic subjects, the
corresponding figures were -13.1(-23.2, -3.1; P=0.01), -14.2 (-22.3, -6.1; P= 0.001) and -
12.7 (-23.5, -1.9; P= 0.021), respectively. Oxygen consumption, estimated in two studies,
showed no significant difference between the treatment groups. Blood lactate levels were
estimated in one study only at two different doses of iron, and were significantly lower
(P<0.05) in iron supplemented group in comparison to placebo both before (7.71 and
7.55 mg/dl versus 8.43 mg/dl) and after (14.36 and 14.35 mg/dl versus 16.48 mg/dl)
exercise. Treadmill endurance time was significantly better in iron supplemented group
when compared with placebo in one study. Thus, iron supplementation may have a
positive effect on the physical performance of children, as evaluated through the post
exercise heart rate in anemic subjects, blood lactate levels and treadmill endurance time.
In view of the limited data availability, this finding cannot be considered conclusive.
Morbidity and Mortality
Relevant information is not available on all the aspects (incidence, duration, or severity)
on which iron supplementation may potentially influence infections. A review included
trials in all age groups of parenteral and oral iron supplements or fortified foods in which
groups differed only in the provision of iron [19]. Oral iron was associated with increased
rates of clinical malaria (5 of 9 studies) and increased morbidity from other infectious
disease (4 of 8 studies). In most instances, therapeutic doses of oral iron were used. No
studies in malarial regions showed benefits while no studies of oral iron supplementation
clearly showed deleterious effects in non-malarious areas. Milk fortification reduced
morbidity due to respiratory disease in two very early studies in non-malarious regions,
but this was not confirmed in three later fortification studies, and better morbidity rates
could be achieved by breast-feeding alone. One study in a non-malarious area of
Indonesia showed reduced infectious outcome after oral iron supplementation of anemic
schoolchildren. No systematic studies reported on oral iron supplementation and
infectious morbidity in breast-fed infants in non-malarious regions.
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Subsequently, a systematic review was conducted, which focused on children only [20].
Evaluated outcome measures included the incidence of all recorded infectious
morbidities. Individual morbidities were also studied, including respiratory tract
infection, diarrhea, malaria, other infections (septicemia, cutaneous infections, worm
infestations, tuberculosis, etc.) and prevalence of smear positivity for malaria. Twenty-
eight studies were evaluated. The pooled estimates (random effects model) of the
incidence rate ratio (IRR) and incidence rate difference (IRD) for all the recorded
morbidities were 1.02 (95% CI 0.96 to 1.08; p=0.54; p for heterogeneity < 0.0001) and
0.06 episodes/ child-year (95% CI -0.06 to 0.18; p=0.34; p for heterogeneity < 0.0001),
respectively. However, there was an increase in the risk of developing diarrhea (IRR=
1.11; 95% CI 1.01 to 1.23; p=0.04), which did not translate into a significant public
health impact (IRD = 0.05 episodes/child-year; 95% CI –0.03 to 0.01; p=0.21). The
occurrence of other morbidities and malarial smear positivity (adjusted for baseline smear
positivity) was not significantly affected by iron administration. On meta-regression, the
statistical heterogeneity could not be explained by a variety of study characteristics.
There was a near absence of any adverse effects, particularly diarrhea, in children
receiving fortified foods (compared with medicinal iron), which raises the possibility of a
dose related effect. The authors concluded that iron supplementation has no apparent
harmful effect on the overall incidence of infectious illnesses in children, though it
slightly increases the risk of developing diarrhea.
An unpublished meta-analysis [21] of 9 published and 4 unpublished randomized
controlled trials using prophylactic oral or parenteral iron supplementation with at least
one P. falciparum related outcome, found a pooled estimate of excess risk from iron
supplementation for incidence of clinical malaria RR 1.09 (95% CI 0.92, 1.3), prevalence
of malaria infection RR 1.17 (95% CI 1.08, 1.25), and absolute change in prevalence of
parasitemia RR 5.7% (95% CI 1.2, 8.5).
Pertinent details of subsequent relevant trials are summarized in Table II. This additional
evidence does not alter the inferences of the earlier reviews. However, the risks and
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benefits of iron supplementation in HIV infection, tuberculosis, and hepatitis C virus
infection have not been extensively studied to make any firm conclusions.
There are no randomized controlled intervention trials evaluating the effect of iron
supplementation alone on mortality. However, two recent recently published and
adequately powered, randomized controlled trials in children below three years of age
have provided information on the effect of routine iron and folate supplementation on
serious morbidity and mortality from Pemba, Zanzibar [26] and southern Nepal [27]. The
African trial was conducted in an area (Pemba) with high malarial transmission (average
of 400 infective bites per year) whereas the Nepal trial was in an area not exposed to any
significant malaria risk.
In the Pemba trial, children aged 1-35 months were assigned to daily oral
supplementation with: iron (12·5 mg) and folic acid (50 micro-grams; n=7950), iron, folic
acid, and zinc (n=8120), or placebo (n=8006); children aged 1–11 months received half
the dose. The primary endpoints were all-cause mortality and admission to hospital. The
iron and folic acid-containing groups of the trial were stopped early on the
recommendation of the data and safety monitoring board. Till that date, 24076 children
contributed a follow-up of 25524 child-years. Those who received iron and folic acid
with or without zinc were 12% (95% CI 2–23, p=0·02) more likely to die or need
treatment in hospital for an adverse event and 11% (1–23%, p=0·03) more likely to be
admitted to hospital; there were also 15% (-7 to 41, p=0·19) more deaths in these groups.
A sub-study was also done with the original objectives of assessing the effects of
supplementation on hematological and zinc status, malaria prevalence, and infectious
disease morbidity. In this sub-study, the overall effect of supplementation with iron and
folic acid was a non-significant reduction in adverse events. The results suggested that
only children with anemia associated with iron deficiency benefited from
supplementation with iron and folic acid with respect to hospital admissions and death.
Those with iron deficiency without anemia were not adversely affected by
supplementation with iron and folic acid, whereas children without iron deficiency had
adverse effects, even in the presence of enhanced detection and management of malaria
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and other infections. Before extrapolating this results widely, it must be realized that the
data pertain to supplementation by iron and folic acid rather than iron alone; the adverse
effects could arise from iron alone, folic acid alone or a combination of both. There are
experimental, laboratory, and field observations that point the finger of suspicion at iron
[29]. However, the supplement was iron and folic acid in a setting in Pemba where the
first line antimalarial treatment was with an antifolate combination of sulfadoxine and
pyrimethamine. The addition of folate to iron plus sulfadoxine and pyrimethamine for the
treatment of malaria results in a biologically and statistically significant delay in parasite
clearance and parasitological (but not clinical) cure [30]. While the dose of folic acid was
an order of magnitude higher in this treatment trial, it is possible that, in an area where
sulfadoxine and pyrimethamine efficacy was declining rapidly, as was likely in Pemba at
the time of the study, folic acid supplementation contributed to the malaria-related
adverse health outcomes of those receiving iron plus folic acid. However, the authors
could not find any association of recovery from sulfadoxine/pyrimethamine treated
malaria episodes or subsequent recrudescence with iron and folic acid versus placebo. In
the absence of a direct comparison of iron with placebo, for the purist, the effect of iron
supplementation alone would remain conjectural.
In the Nepal trial, 1 to 36 months old children were randomly assigned to daily oral
supplementation with: iron (12·5 mg) and folic acid (50 micro-grams; n=8337), zinc
alone (10 mg), iron, folic acid, and zinc (n=9230), or placebo (n=8683); children aged 1–
11 months received half the dose. The primary outcome measure was all-cause mortality,
and secondary outcome measures included cause-specific mortality and incidence and
severity of diarrhea, dysentery, and acute respiratory illness. A total of 25490 children
had participated till the time that the trial was stopped early and analyses are based on
29097·3 person-years of follow-up. There was no difference in mortality between the
groups who took iron and folic acid without or with zinc when compared with placebo
(HR 1·03, 95% CI 0·78–1·37, and 1·00, 0·74–1·34, respectively). There were no
significant differences in the attack rates for diarrhea, dysentery, or respiratory infections
between groups, although all the relative risks except one indicated modest, non-
significant protective effects. The authors concluded that daily supplementation of young
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children in southern Nepal with iron and folic acid with or without zinc have no effect on
their risk of death, but might protect against diarrhea, dysentery, and acute respiratory
illness.
An expert WHO meeting convened specifically to examine these two trials [31],
concluded that in regions with a high prevalence of malaria and other infections, iron and
folic acid supplementation for young children be targeted to those who are iron deficient.
Every effort should also be made to combine iron supplementation with effective
treatment and control of malaria and other severe infectious and parasitic disease. It was
also emphasized that these findings should be regarded as specific to iron and folic acid
supplementation of young children in regions of the world where malaria transmission is
intense and severe infectious disease prevalence is high. The conclusions should not be
extrapolated to fortification or food-based approaches for delivering iron. Thus, iron
administration slightly increases the risk of developing diarrhea (IRR 1.11). In non-
malarious regions iron supplementation has no apparent beneficial or harmful effects on
the overall incidence of infectious illnesses in children. In malarious regions, particularly
those with high transmission rates, iron supplementation may result in increased risk of
malarial infection. In populations with high rates of malaria, routine supplementation
with iron and folic acid in preschool children can result in an increased risk of severe
illness and death. However, in the presence of an active program to detect and treat
malaria and other infections, iron deficient and anemic children can benefit from iron and
folic acid supplementation. In areas where iron deficiency is common and malaria absent,
daily supplementation of young children with iron and folic acid has no effect on their
risk of death, but might protect against diarrhea, dysentery, and acute respiratory illness.
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Biological Consequences of Maternal Iron Deficiency as Assessed by Iron Interventions
Work Capacity in Non-Pregnant, Non-Lactating Women
The causal relationship between iron deficiency and physical work capacity has been
evaluated through a systematic review of the research literature, including animal and
human studies [32]. Although the review examined human subjects of various ages and
both genders, the inferences appear to be valid for the sub-set of non-pregnant, non-
lactating women. Iron deficiency was examined along a continuum from severe iron-
deficiency anemia (SIDA) to moderate iron-deficiency anemia (MIDA) to iron deficiency
without anemia (IDNA). Work capacity was assessed by aerobic capacity, endurance,
energetic efficiency, voluntary activity and work productivity. The 29 research reports
examined demonstrated a strong causal effect of SIDA and MIDA on aerobic capacity in
animals and humans. The presumed mechanism for this effect is the reduced oxygen
transport associated with anemia; tissue iron deficiency may also play a role through
reduced cellular oxidative capacity. Endurance capacity was also compromised in SIDA
and MIDA, but the strong mediating effects of poor cellular oxidative capacity observed
in animals have not been demonstrated in humans. Energetic efficiency was affected at
all levels of iron deficiency in humans, in the laboratory and the field. The reduced work
productivity observed in field studies is likely due to anemia and reduced oxygen
transport. The social and economic consequences of iron-deficiency anemia (IDA) and
IDNA have yet to be elucidated. The reviewers concluded that biological mechanisms for
the effect of IDA on work capacity are sufficiently strong to justify interventions to
improve iron status as a means of enhancing human capital. A critical review of this
report also concluded that from both the laboratory and field experiments, the evidence is
strong and suggests that the potential magnitude of the effect of iron-deficiency anemia
on work productivity is substantial [33]. Thus, iron supplementation in non-pregnant,
non-lactating women suffering from severe or moderate iron deficiency anemia improves
work capacity.
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Hemoglobin and Anemia
A systematic review [34] evaluated change in hemoglobin levels with randomized
controlled trial design interventions. Only 23 studies, 15 of which were conducted in
developing countries met the inclusion criteria. The average baseline hemoglobin level of
women in 13 of the 15 randomized controlled trials conducted in developing countries
was below 11 g/dl. Relative to no supplementation, iron supplementation alone increased
hemoglobin change by 1.0 + 0.013 g/dl (P < 0.001, n=1118, df =13). In the three studies
reporting on iron deficiency, iron supplementation alone reduced the percentage of
women with hemoglobin levels of less than 11 g/dl by 38% (the mean effect on
hemoglobin change was 1.2 g/dl). The effect was greater with lower baseline hemoglobin
levels and there was evidence of a dose response relationship (greater effect in studies
providing supplementation for longer duration). Another subsequent systematic review
from Cochrane database [35] found that iron supplementation in pregnancy raised or
maintained the serum ferritin above 10 milligrams per liter, and prevented low
hemoglobin at birth or at six weeks post partum. Observational data and a few relevant
controlled trials, indicate that maternal iron status has a positive impact on the neonatal
iron stores [36-38]. Thus, iron supplementation in pregnancy increases the maternal iron
stores, and prevents low hemoglobin at birth or at six weeks post partum. The effect is
greater with lower baseline hemoglobin levels and with longer duration of
supplementation. Iron administration in pregnancy also has a positive impact on the
neonatal iron stores.
Maternal Mortality and Morbidity
Relevant evidence in this context is only observational in nature. The available data
confirm an associative – not causal – relationship between severe anemia (hemoglobin
concentrations below 7 or 8 g/dl) and the risk of maternal mortality [37]. Nevertheless the
strength of this relationship makes it appropriate to presume that it is causal. However,
routine iron supplementation has not been shown to reverse severe anemia; thus the
potential benefit of iron administration in reducing maternal mortality is questionable.
The evidence of a relationship between maternal death and moderate anemia, however, is
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both scanty and contradictory. Until further data are available, it appears that moderate
concentrations of anemia are probably best considered unrelated to excess maternal
mortality; thus there is no likely benefit of iron supplementation in this context. There is
negligible evidence evaluating the effect of iron administration on prevention or
treatment of maternal morbidity other than anemia [39].
Recent preliminary evidence, primarily from observational studies in developed
countries, has linked maternal iron supplementation and increased iron stores to
gestational diabetes mellitus and increased oxidative stress during pregnancy [40]. The
possibility that prophylactic iron supplementation may increase risk of maternal
morbidity when there is no iron deficiency or iron deficiency anemia, deserves
exploration through relevant intervention trials. Thus, iron administration in pregnancy is
not likely to reduce maternal mortality or morbidity other than anemia. The possibility
that prophylactic iron supplementation may increase risk of gestational diabetes mellitus
when there is no iron deficiency, deserves exploration.
Newborn Size and Gestation, and Perinatal Health Strong evidence exists for an association between maternal hemoglobin concentration
and birth weight as well as between maternal hemoglobin concentration and preterm birth
[41]. From the available data, it is not possible to determine how much of this association
is attributable to iron deficiency anemia in particular. Minimal values for both low birth
weight and preterm birth occurred at maternal hemoglobin concentrations below the
usual cut-off value for anemia during pregnancy (11 g/dl) in a number of studies,
particularly those in which maternal hemoglobin values were not controlled for the
duration of gestation. In randomized controlled trials, iron supplementation of anemic or
non-anemic pregnant women had no detectable effect on either birth weight or the
duration of gestation or perinatal morbidity and mortality [35,42]. However, the
individual information on neonatal and perinatal outcomes is available in only a limited
number of studies, especially from communities where iron deficiency is common.
Further, the available studies need to be interpreted with caution because most are subject
to a bias towards false-negative findings.
18
Observational data on anemia imply that iron supplementation should be started early in
pregnancy, if not before, to improve neonatal and perinatal outcomes [39]. An important
limitation of adequately designing iron intervention studies in pregnancy has been the
exclusion of women with anemia at baseline, and/or lack of a placebo group due to
ethical concerns [36]. Using an innovative approach to limit this problem, an intervention
trial was conducted in Cleveland, Ohio [42] that provided 30 mg iron daily from < 20
weeks to 28 weeks of gestation. A placebo group was included because women found to
have a hemoglobin concentration <10 g/dl or ferritin <20 micrograms/ liter at 28 weeks
or 38 weeks of gestation were supplemented with iron. Iron supplementation from
enrollment through 28 weeks of gestation did not affect the prevalence of anemia but
increased birth weight by 206 g and gestation by 0.6 weeks. The trial documented a
lowered incidence of low birth weight from 17% to 4% while preterm delivery incidence
was not lowered. In Nepal, another cluster-randomized study with early supplementation
arrived at a similar, but not identical result [43]. In comparison to controls, gravidas
receiving folate showed no reduction in the risk of low birth weight, whereas those
receiving iron plus folate increased birth weight by 37 g and showed a reduction of 14%
in risk of low birth weight. Preliminary intervention evidence thus suggests that early
supplementation with iron can increase birth weight and gestational duration with
concomitant reduction in risk of low birth weight or preterm low birth weight but not
preterm delivery.
Evidence, primarily from observational studies in developed countries, has linked
increased maternal hemoglobin and/or iron stores and iron supplementation to impaired
fetal growth [37,41]. The possibility that prophylactic iron supplementation may impair
fetal growth when there is no iron deficiency deserves exploration through relevant
intervention trials. Thus, there is no conclusive evidence that routine iron
supplementation in pregnancy will increase newborn size and duration of gestation, and
improve perinatal health. However, this information is available from a limited number of
studies, which are subject to a bias towards false-negative findings. Preliminary
intervention evidence suggesting that early supplementation can increase birth weight and
19
duration of gestation needs urgent validation. The possibility that prophylactic iron
supplementation may impair fetal growth when there is no iron deficiency also deserves
exploration.
20
Relative Efficacy of Intermittent and Daily Iron Supplementation for the Control of Iron Deficiency Anemia in Developing Countries
The relative efficacy of intermittent and daily iron supplementation for the control of iron
deficiency anemia in developing countries has been examined in a meta-analysis of 22
completed trials involving nearly 6000 subjects [44]. The review examined results in the
individual projects, grouped into three categories: pregnant women, school children and
adolescents, and preschool children. Both weekly and daily iron supplementation were
efficacious in reducing anemia. However, weekly iron supplementation was less effective
than daily iron supplementation in reducing anemia; the pooled relative risk of being
anemic at the end of the intervention with weekly dosing was 1.34 (95% confidence
interval 1.20 – 1.49). With both forms of supplementation, compliance was an important
predictor of hemoglobin response. A pertinent review of subsequent iron supplementation
trials comparing daily versus intermittent administration is summarized in Table III [13,
24, 45-62], which reaffirms the main conclusion of the earlier systematic review [44].
Thus, daily iron supplementation is more efficacious than intermittent iron administration
for the control of anemia in developing countries.
Recently, an evaluation has been published of the pilot programs initiated in some States
of India to demonstrate effectiveness and feasibility for scale-up of weekly iron (100mg
ferrous sulphate) and folic acid (500 micrograms) supplementation in adolescent girls
[63]. Impact assessments were conducted in seven of the programs, and were based on
reported compliance with tablet intake and on the analysis of hemoglobin concentration.
Randomly selected (non-paired) samples for hemoglobin measurements were collected
before the start of the programme and 12-14 or 24 months after programme initiation. In
some cases, a large impact was reported, as in Andhra Pradesh, with a decrease in
prevalence of anemia by 70% in two years. In some other states, the impact after one year
was more modest. It was concluded that that weekly supplementation of adolescent girls
with iron and folic acid tablets did lead to a marked decrease in the prevalence of anemia.
Conclusions
A summary of the major conclusions of the review is articulated in Table IV.
21
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28
Table I. Effect of Iron Supplementation on Mental and Motor Development
(Additional RCTs).
Author Year Country Subjects Dose
Follow up
time Outcomes evaluated Conclusions
Friel9 2003 Canada
77 term breast fed neonates, preterm & low birth weight
excluded 7.5 mg/d for
5 months
12-18 months of age
CBC, SF, red cell
superoxide dismutase, catalase,
plasma ferric reducing
antioxidant power, zinc and copper
levels, BSID, visual
acuity
Higher Hb & MCV at 6 months in iron group
(no difference at other times), higher PDI at 13 months of
age, no difference in
other parameters, recruitment
stopped before
sample size adequate due
to lack of funds
Black10 2004 Bangladesh
346 infants, ~6 months,
18% stunted, none wasted, 68% anemic;
severely malnourished
& severely anemic
excluded
Iron (20 mg/d), zinc (20 mg/d), iron and
zinc, micronutrient
mix or placebo.
6 months
BSID II, HOME scale (behaviour)
Iron & zinc in
combination resulted in
better development.
However, given alone each had a significant effect on
orientation engagement
only. No effect on Hb.
Lind11 2004 Indonesia
680 infants, <6 months, Hb<9 g/dl excluded; stunting,
underweight & wasting
<5%.
10 mg iron/d, 10 mg
Zinc/d, both, or placebo
6 months
BRS, BSID, PDI
Higher PDI in iron
group, no effect on MDI and
BRS
Metallinos-Katsaras12 2004 Greece 49, 3-4 year 15 mg/d
2 months
Simple reaction time
test, continuous
performance task, oddity
learning tasks
After iron treatment,
anemic subjects
made fewer errors of
commission, exhibited
higher
29
Author Year Country Subjects Dose
Follow up
time Outcomes evaluated Conclusions
accuracy and were
significantly more
efficient. No effect in iron
replete subjects. No effect on the
oddity learning task
Sungthong13 2004 Thailand
397 primary school
children, severe iron deficiency anemia and
severe malnutrition
excluded, anemia 27%, thalessemia trait 17%
60 mg iron 1d/week, 5d/week, placebo
16 weeks
Hb, SF, IQ, language,
mathematics
Comparable & significant increase in
Hb in weekly and daily
iron groups, SF increment most in daily iron group &
least in placebo
group. IQ increment
least in daily iron group
(weekly iron group and
placebo had similar
increase). No effect on school
performance.
Zhou14 2006 Australia
430 pregnant women (20
wk) 20 mg/d till
delivery 4 year
Stanford-Binet
Intelligence Scale,
Strength and Difficulties
Questionnaire
No effect on intelligence,
increased abnormal
behavior in iron group
BSID: Bayley`s scale of infant development; BRS: Behaviour rating scale; CBC: Complete blood count; IDA: Iron deficiency anemia; Hb: Hemoglobin; IQ: Intelligence quotient; MCV: Mean corpusclar volume; MDI: Mental development index; PDI: Psychomotor development index; SF: Serum ferritin
30
Table II. Effect of Iron Supplementation on Infectious Morbidity in Children (Additional RCTs).
Author Ye
ar Coun
try Subjects Dose
Follow up Outcome
Richard22
2006 Peru
855, 6 mo-15 years
Increased morbidity due to Plasmodium vivax and diarrhea in children >5yr. In children <5 year, iron+zinc provided protection against P. vivax, but iron interfered with diarrhea protection
associated with zinc. No effect on the incidence of respiratory infection.
Lopez de
Romana23
2005 Peru
313, 6-12 mo; preterm, low birth weight;
severely wasted and
severely anemic
excluded
10 mg/d iron, daily multiple
micronutrient, weekly multiple
micronutrient, placebo
6 mont
hs
Hemoglobin increased significantly in all experimental groups (no difference
in weekly & daily iron groups), no significant difference in change in
serum ferritin. Anemia decreased in all experimental groups with greater decrease in the daily iron group
compared to weekly iron group. Iron status better in the daily iron group than
in placebo or weekly iron group. No difference in the monthly prevalence of
diarrhea, acute respiratory infection, and fever
Untoro2
4 2005
Indonesia
284, 6-12 months (58%
anemic)
Multiple
micronutrient supplements daily,
multiple micronutrients
weekly, 10 mg iron daily, placebo
6 mont
hs No difference in respiratory infection,
diarrhea and fever.
Mebrahtu25
2004
Zanzibar
614, 4-71 mo, 94.4% anemic, 48.1% stunted, >80% malaria
positive 10 mg/d
12 mont
hs
No difference in various malariometric indices or any malarial infection
outcome.
Lind10 2004
Indonesia
680 infants, <6 months; Hb<9 g/dl excluded;
stunting, underweight & wasting <5%.
10 mg iron/d, 10 mg Zinc/d, both, or
placebo
6 mont
hs
No significant difference in the incidence of diarrhea and lower
respiratory infection
Baqui26 2003
Bangladesh
799, 6 months; Hb<9 g/dl, MUAC <11 cm excluded
20 mg/wk iron+1 mg riboflavin (rb), zinc+
rb, iron+zinc+rb, iron+zinc+rb+MM,
rb as control 12 mo
Iron & zinc alone had no effect on
morbidity. However, iron + zinc group had a lower rate of severe diarrhea in all infants and a lower rate of severe
lower respiratory infection in malnourished
31
Table III. Trials Comparing the Effect of Daily versus Intermittent Iron Supplementation in
developing Countries (Additional RCTs).
Author Year Country Subjects Dose Follow
up Conclusion
Kianfar45 2000 Iran
260 anemic & 260 non-anemic
school girls
50 mg daily, weekly & twice
weekly 3 months
Significant increase in Hb in all experimental groups (no difference between experimental
groups), significant increase in SF in all experimental groups (daily iron group had more increment than weekly iron groups).
Mumtaz46 2000 Pakistan
191 pregnant women, 17-35 years, Hb<11
g/dl 60 mg daily, twice weekly 12 weeks
Rise of Hb significant only in the daily iron
group.
Zavaleta47 2000 Peru
312 Girls 12-18 years, Hb> 8
g/dl 60 mg 5d/wk, twice weekly 17 weeks
Hb increments higher with increased frequency than intermittent iron, but SF and FEP were similar between the two groups.
Goonewardene48 2001 Sri Lanka
92 pregnant women (12-24
weeks)
100 mg weekly vs thrice weekly
vs daily 12 –20 weeks Daily better
Ekstrom49 2002 Bangladesh
50 antenatal centers, 140
pregnant women 60 mg daily vs 120 mg weekly 3 mo
Daily iron group had higher Hb levels at 12
weeks. No difference in prevalence of anemia.
Ermis50 2002 Turkey 113 infants more
than 5 mo
1 mg/kg/day vs 2 mg/kg/day vs
2 mg/kg alternate day 3 mo
Hematological values (except Hb) higher in 2
mg/kg/day group, ferritin values higher in 2 mg/kg alternate day
group
Nguyen51 2002 Vietnam 270,
5-12 mo 15 mg daily vs 15 mg weekly 6 mo Daily better
Shah52 2002 Nepal
209 adolescent
girls 11-18 years, ~50%
anemic
350 mg
FeSO4/d for 100 days,
weekly for 14 weeks
14 weeks
Rise of Hb, Hct and
prevalence of anemia in post supplementation period comparable in
both groups.
Sungthong53 2002 Thailand 397 primary
school children 300 mg FeSO4 daily vs weekly 16 weeks
Height gain better in weekly group
Haidar54 2003 Ethiopia
207 lactating women from urban slums
60 mg daily vs 5 d/week No difference
2003 Turkey 95, 6-60 months, 6 mg/kg daily 2 months
32
Author Year Country Subjects Dose Follow
up Conclusion Tavil55 Hb <10 g/dl,
TS< 12%, SF< 12 ng/ml
or twice weekly No differences between Hb, Hct, MCV, MCHC,
SI & SF in the 2 experimental groups.
However; RDW, SIBC, TS, transferrin receptor,
and transferrin receptor/log ferritin better in intermittent
group.
Desai56 2004 Kenya
1049,
2-59 months with mild to
moderate anemia (Hb 5-10.9 g/dl); 31%, 7.1% and 23.2% stunted,
wasted & underweight, respectively,
~60% malaria positive
3-6 mg/kg daily vs 6-12 mg/kg twice weekly 6 weeks
No difference in malarial and non-
malarial morbidity. Daily iron resulted in
greater increase in Hb.
de Souza57 2004 Brazil
150 pregnant women, 13-38 years Hb 8-11
g/dl, 16-20 weeks
pregnancy
60 mg daily, weekly, twice
weekly 16 weeks
Both Hb & MCV increased more in the daily iron group. SF
increase was comparable in all three
groups (SF was not comparable at entry into
the trial).
Mukhopadhyay58 2004 India
111 Pregnant women (< 20
weeks) 100 mg/d vs 200 mg/wk
Till 34 wk
gestation
Greater rise of Hb in anemic subjects in daily iron group, higher SF in
daily iron group, no difference in mean birth
weight, period of gestation and mode of
delivery
Pena-Rosas59 2004 Venezuela 16 pregnant
women
60 mg twice weekly vs 120
mg weekly
Till 36-39 wk
gestation
No difference in Hb, SF and Hct. Transferring
saturation more in twice weekly group.
Siddiqui60 2004 Pakistan 60,
5-10 years 200 mg FeSO4 daily vs weekly 2 mo No difference
Sungthong13 2004 Thailand
397 primary school children, severe IDA and
severe malnutrition
excluded, anemia 27%,
thalessemia trait 17%
60 mg Fe 1d/wk, 5d/wk,
placebo 16 weeks
Comparable &
significant increase in Hb in weekly and daily
iron groups, SF increment most in daily
iron group & least in placebo group. IQ
increment least in daily iron group (weekly iron group and placebo had
33
Author Year Country Subjects Dose Follow
up Conclusion similar increase). No
effect on school performance, language & mathematical ability.
Yang61
2004
China
353 Preschool
children
Daily iron or once weekly
iron or placebo
14 weeks
Iron deficiency
reduction and weight gain better in daily iron, No difference in height
gain, Hb
Yurdakok62 2004 Turkey
79, 4mo old, exclusively breast-fed
healthy infants excluding
preterm, low birth weight
infants & infants of mothers who
were iron deficient
1 mg/kg daily vs 7 mg/kg
weekly for 3 months 6 mo No difference
Untoro24 2005 Indonesia
284, 6-12 months (58%
anemic)
Multiple micronutrient daily (DMM),
multiple micronutrient
weekly (WMM), 10 mg iron daily (DI),
placebo 6 months
DMM & DI had higher Hb post-treatment compared with baseline; however, the changes in Hb were not significantly different from placebo. SF increase most with DI & least with WMM (DMM better than WMM).
FEP: Free erythrocyte protoporphyrin; Hb: Hemoglobin; Hct: Hematocrit; IQ: Intelligence quotient; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; RDW: Red cell distribution width; SF: Serum ferritin; SI: Serum iron; SIBC: Serum iron binding capacity; TS: Transferrin saturation.
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Table IV. Summary of key conclusions of the iron review.
Issues or questions Conclusions Quality of evidence
What are the efficient indicators of population response to iron interventions?
Hemoglobin and ferritin are currently the most efficient combination of indicators for monitoring population response to iron interventions, and these may have economic and logistic benefits in less developed countries.
1+
Iron deficiency is only one of the important causes of anemia. What is the effect, if any, of iron supplementation on hemoglobin response in children, and can effect predictors be identified to aid public health decisions?
Iron supplementation increases hemoglobin levels in children significantly, but modestly. The rise is greater with baseline anemia, and lower in malarial hyperendemic areas and in those consuming iron fortified food. The projected reductions in prevalence of anemia with iron supplementation alone (38% to 62% in non-malarial regions, and 6% to 32% in malarial hyper-endemic areas) highlight the need for additional area-specific interventions, particularly in malarial regions.
1++
What is the effect of iron administration on mental and motor development in children?
Iron supplementation improves mental development score modestly (standardized mean difference of 0.3, equivalent to 1.5 to 2 points on a scale of 100). This effect is particularly apparent for intelligence tests above seven years of age, and in initially anemic or iron deficient anemic subjects. There is no convincing evidence that iron treatment has an effect on mental development in children below 27 months of age, or on motor development. However, (i) there is a suggestion of an improvement in subtle developmental measures like oddity learning test and orientation engagement, which are not encompassed by the traditional tests; (ii) confidence intervals suggest that these results could be compatible with moderate positive or adverse effects of iron therapy; (iii) the possibility of irreversible structural brain changes, particularly in younger children cannot be excluded due to paucity of relevant preventive trials; and (iii) the effect of longer term treatment is unclear.
1++
What is the effect of iron administration on physical growth in children?
There is no convincing evidence of a positive effect of iron supplementation on the physical growth of children.
1++
What is the effect of iron administration on physical performance in children?
Iron supplementation may have a positive effect on the physical performance of children, as evaluated through the post exercise heart rate in anemic subjects, blood lactate levels and treadmill endurance time. In view of the limited data availability, this finding cannot be considered conclusive.
1++
35
Issues or questions Conclusions Quality of evidence
What is the effect of iron administration on morbidity and mortality in children?
Iron administration slightly increases the risk of developing diarrhea (11%). In non-malarious regions iron supplementation has no apparent beneficial or harmful effects on the overall incidence of infectious illnesses. In malarious regions, particularly those with high transmission rates, iron supplementation may result in increased risk of malarial infection. In populations with high rates of malaria, routine supplementation with iron and folic acid in preschool children can result in an increased risk of severe illness and death. However, in the presence of an active program to detect and treat malaria and other infections, iron deficient and anemic children can benefit from iron and folic acid supplementation. In areas where iron deficiency is common and malaria absent, daily supplementation of young children with iron and folic acid has no effect on their risk of death, but might protect against diarrhea, dysentery, and acute respiratory illness.
1+ to 1++
What is the effect of iron administration on work capacity in non-pregnant, non-lactating women?
Iron supplementation in non-pregnant, non-lactating women suffering from severe or moderate iron deficiency anemia improves work capacity.
2++
What is the effect, if any, of iron supplementation in pregnancy on maternal and neonatal hemoglobin response and iron stores, and can effect predictors be identified to aid public health decisions?
Iron supplementation in pregnancy increases the maternal iron stores, and prevents low hemoglobin at birth or at six weeks post partum. The effect is greater with lower baseline hemoglobin levels and with longer duration of supplementation. Iron administration in pregnancy also has a positive impact on the neonatal iron stores.
1++
2++
What is the effect, if any, of iron supplementation in pregnancy on maternal mortality and morbidity other than anemia?
Iron administration in pregnancy is not likely to reduce maternal mortality or morbidity other than anemia. The possibility that prophylactic iron supplementation may increase risk of gestational diabetes mellitus when there is no iron deficiency, deserves exploration.
2-
What is the effect, if any, of iron supplementation in pregnancy on newborn size, duration of gestation and perinatal health?
There is no conclusive evidence that routine iron supplementation in pregnancy will increase newborn size and duration of gestation, and improve perinatal health. However, this information is available from a limited number of studies, which are subject to a bias towards false-negative findings. Preliminary intervention evidence suggesting that early supplementation can increase birth weight and duration of gestation needs urgent validation. The possibility that prophylactic iron
1-
2-
36
Issues or questions Conclusions Quality of evidence
supplementation may impair fetal growth when there is no iron deficiency also deserves exploration.
Is intermittent iron supplementation as effective as daily iron administration for the control of anemia in developing countries?
Both daily and intermittent iron supplementation are efficacious in reducing anemia in developing countries. However, daily iron supplementation is more efficacious than intermittent iron administration.
1 ++
Levels of Evidence
1++ High quality meta analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias
1+ Well conducted meta analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
1 - Meta analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
2++ High quality systematic reviews of case-control or cohort or studies High quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal
2+ Well conducted case control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal
2 - Case control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal
3 Non-analytic studies, e.g. case reports, case series
4 Expert opinion